Anesthetic compounds, intermediates, and processes therefor



Patented Nov. 21, 1944 UNVITED" STATE s PATENT orries ANESTHETIC COMPOUNDS INTERMEDI- ATES, AND PROCESSES THEREFOR William FfBingk, Hollis, N. Y., assignor to Novor l col Chemical Mfg. Co., Inc.,. Brooklyn, N. Y., a

corporation of New York No Drawing. Application August 9, 1941, Serial No. 406,182

4 Claims. (01. 260-472) intermediates and processes therefor.

The principal object ofthe present. invention is to produce a series of new compounds and in- This invention relatesto anesthetic compounds,

termediates, as well as to. produceza simple practical process for the manufacture of the same. Although boththe intermediates and compounds are primarily intendedfor production of local anesthetics, their use. is not restricted thereto..

The invention comprisesIthe novel products, the specific embodiments of which are described hereinafter by way of example and in accordance with which I now prefer to practice the invention.

i I have found in accordance with my invention. a series of substances having the formulae:

. CH3 NEHLCtHlLC 0 0 ore-one Alkyl R Neg-canto o OCHi.(:J.NH Alkyl B/f where R=H and R"=Inethyl or ethyl;

where R =a lower alkyl group. In each instance,"

NH Alkyl contains not more than ten carbon atoms.

These compounds are useful as anesthetics,

though not restricted to such use, and are made from the reaction of ethanols. with nitro benzoyl.

halides at set forth hereinafter.

Compounds falling under group 1 above are claimed herein. Compounds falling under group i 2 are claimed inmy copending application Serial No. 496,589, filed July 29, 19.43. Compounds falling under group Bare claimed in. my copending.

application SeriaTNo. 472,963 filed January 20, 1943*. N

These anesthetics, especially the higher members of the series, that is containing a relatively large number of carbon atoms in thealkyl group, are particularly valuable assurface anesthetics The intermediates used in preparing the above substances. are prepared in accordance with my invention through the reaction. between aseries of .alkylhalides and ethanols. described. below.

and find special use accordingly in operations I such as those-ontheeye; Compared with butyny which is often employed for eye operations, these These in turn are reacted. with. nitro. benzoyl halides as described. below. i

In preparing these. ethanols, the reaction mixtures arerefiuxed mama to 96hours, depending upon the molecular Weight of. thealkyl group. en.- tering the molecule. I-t isimportant to use anexcess of the alkyl halide, generally two mols of. halide to one of the ethanol, in. order to force,

the reaction. to form the desired compound. The

followingis an outline of the procedure used'in preparing some membersof this series.

1. Preparation of-beta-ethyl amino beta, beta- .dimethyl ethanol- CH3 n0.cH2.c :NHo.H.

s s Hz i To 178- grams. (2. mols) of beta-amino beta,

beta-dimethyl ethanol and 436 grams (4 mols) of ethyl bromide contained. in a fiaskwas added 900 cc. of water. The reaction mixture was allowed ing of unreacted ethyl bromidewas separateda 6. saved, an excess overthe amount requiredto. neutralize the HBr, of sodium hydroxide. was added with. cooling to the fraction remaining in. the separatory funnel. A white solid. mass separated from the caustic solution which was then extracted, with. ether,,,the ether layer separated,

dried over anhydrous sodium sulfate and the. ether evaporated off. Theresidue was vacuum distilled and the fraction boiling at 84-93" C. at 21 24 mm. pressure was saved.

On careful fractionation, this yields a pure secondary amino alcohol which has a B. P. (boiling point) 167-169? C. at atmospheric pressure. It is a white solid having an M. P. (melting. point) at. 54.5-57.0 C. and when sublimed gives white, hygroscopic needles'vzith a slight ammoniacal odor.

of normal prom/l amino beta di- "methyl ethanol To .178 grams (2 mols) of beta amino beta beta dimethyl ethanol and 492. gramsrfli mols) of normal propyl bromide contained in a flask was added .900. grams. of isopropanol. The reaction mixture was allowed ,to reflux for '24 hours and 2. Preparation cooled. An excess of concentrated hydrochloric acid was added to the reaction mixture and the mixture vacuum-distilled to. remove all the water and isopropanol. To the residue remaining in the flask, an excessover the amount required to neutralize the added acid, of a l 30% caustic alkali I reaction without any solvent.

solution is added. A white solid mass was separated from the caustic solution, This white solid mass was then extracted with ether. The ether layer was separated, dried over a suitable dryingagent such as anhydrous sodium sulfate, and the ether evaporated off. The residue was vacuumdistilled under reduced pressure and the distillate ,was carefully fractionated and yielded a pure secondary amino alcohol boiling at 181-186 C.- and melting at 47-49 .C. It is a white solid and when sublimed gives white, hygroscopic needles with a slight ammoniacal odor. The compound has the following formula:

It will be noted in accordance with the above examples that where the beta alkyl group attached to the nitrogen atom is ethyl, as in Example 1, that water is preferably used as a solvent. Where the compound contains a propyl group instead of the ethyl group as in Example 2, isopropanol or similar inert solvent is employed. Instead of isopropanol, I may employ normal propanol or methanol. For the higher members of the series, that is, Where such alkyl group contains 5 or more carbon atoms, 1. e., starting with the amyl compounds, I prefer to carry out the For instance, in the preparation of the voctyl compound, I use'the following procedure:

3. Preparation of beta (alpha-methyl heptyl) amino beta, beta dtmethyl ethanol To 54 grams (0.6 mol) of beta amino beta beta dimethyl ethanol isv added 117 grams (0.65 mol) 5A. Beta (sec. butyl) amino beta, beta-dimethyl ethanol of. Z-brom-octane andthis mixture refluxed for six hours and then allowed to cool. An excess of a 30% caustic alkali solution is added to the reaction mixture in the flask which causes the separation of a yellow liquid. This is extracted with ether. The ether layer is separated and dried over a suitable drying agent, such as anhydrous sodium sulfate. The ether is evaporated and the residue vacuum-distilled. On careful fractionation, thereis obtained a pure secondary amino alcohol boiling at 250-255 C. The specific gravity at 20 C. is 0.8715. The refractive index at 20 C. is 1.4516. The compound has the following formula:

' In a manner similar to the above described preparation, the other members of this series were prepared as follows:

4. Beta-isopropyl amino beta, beta-dimethyl ethanol CH: HO.CH2.CNHC3H1(iS0) H: B.r6=173-177 0. m (refractive index)=l.4442. M. P. =40 T 5. Beta-normal butt/l amino beta, beta-dimethyl ethanol HO.CHa.( J-NHC4Ha(n) M. P.=64:.567.0 C. B. P.=200203 C.

6. Beta-isobutyl amino beta-beta-dtmethyl ethanol CH3 HdCHaC-NHClHfliSO) H: M. P.=40.0-43.5 C. B. P..=194-196 C.

7. Beta-normal amyl amino beta, beta dimethyl ethanol on; HO CHaC-NHCsHuOI.)

8. Beta-isoamyl amino beta, beta-dimethyl ethanol CH3 7 HO.CHg.( J-NHC5H11(iS0) Ha M. P.=58.0-64.5 C. B. P.=211215 C.

9. Beta-normal hea'yl amino beta, beta-dimethyl ethanol CHa HO.QHL(IJNHCQH1E(IL) M. P.=58.6-60. 0 C. B. P.=235-238 C. 10. Beta (ethyl butyl) amino beta, beta dtmethyl ethanol on; em,

noomcaqnomcn 113 can This is a liquid compound having the following constants:

B. P. at atmospheric pressure=22022 6C.. D 0.8858.

11. Beta-normal heptyl amino beta, beta dimethyl ethanol 13. Beta normal decyl amino beta, beta-dimethyl ethanol OH: HO CHI-( 3 .NH.CmHn(n.)

This is a solid material having an M. 11:50-53 c. B. P. at 760 mm.=295-300 c.

The above. alkylammo ethanolaare members of the beta allwliamino beta beta dimethyl ethanol series. In a'similar manner to that employed, for the preparation of this series, the beta alkyl amino beta methyl ethanolserles .may be prepared, using the, known beta amino beta methyl These amino alcohols are all colorless liquids with a slight:aminoniacal-odor and give a-positive ethanol as one of the starting materials and reacting this with the corresponding alkyl halide, which is also known. Using this method the following secondary amin alcohols were prepared, having the followingconstants: a

14. Betaanormalamylamino-beta-methyl; ethanol B. P.=2l0 220 G."at"atmosphoric pressure; D

15. Beta isoamyl amino beta-methyl ethanol H noomg s nacmn V OH: H

nitroso test for secondary amino nitrogen.

The above-mentioned ethanols are condensed with the nitro ,ben zoylhalide in order to produce the corresponding nitro benzoates which on reduction with tin or iron and hydrochloric acid constitute useful anesthetic bases.

20. Preparation of beta, ethyl amino beta, betadimethylethyl para nitro benzoate To 20 gramsof beta-ethyl amino' beta beta dimethyl ethanol, 8 gramsof sodiumhydroxide and 400 cc. of water wasadded all. at one time with B. P.=2062l4 C. at atmospheric pressure. I) 0.8812.

ethanol, which is known, and reacting it with an alkyl halide, corresponding beta alkylamino alpha beta dimethyl ethanols have been prepared as follows: it

16.: Beta-normal, butylgamino; alpha; beta-dz- ,.-.=;meth1/Z.ethanol... r

B. 1 .=197-2o5 0. at atmospheric pressure. 13, =0.ss9a.

l7. Beta-isobutyl amino alpha, beta-dimethyl t ethanol) 1 R F: 110.0 C .NH( J 4Hq(iso) "onion: c c B. P.=179 1src; m g 3711. 11, -14399.

18. Beta-normal amyl amino alpha, beta-aimethyl ethanol H: CH: B. r.= 212 22o o. at atmcspheric, pressure. 13%?05763. HEILFIAMZ- are 19. Beta-isoahwl amino alpha, beta-dimethyl ethanol A B E H01 dmromuasw 7 CH: Ha

B. P.=2062l3 atmospheric pressure. D =0.8 574.

. ture is filteredto remove the iron sludge. About solidifies.

v Similarly, using beta amino alpha beta dimethyl vigorousstirring, 32" grams of finely pulverized para nitro benzoyl chloride. The temperature of the reaction mixture is maintained between 30-40 C. and stirring continued until the ,nitro ester The nitro ester' is filtered, off and washed with water until free from alkali.

The nitro ester formed above may be reduced by conventional methods, using for instance, tin and hydrochloricacid, but is preferably reduced as follows: 1

35 gramsof betaethyl amino beta, beta-dimethyl ethyl para nitro benzoatefl'lO. grams of iron filings, 9.5 cc. of concentrated hydrochloric acid and 600 cc. of water are placed in a breaker and stirred vigorously: The initial heat of reactionis not permitted tosgo above 50 C. When the temperature of the reaction mixture starts to fall, heat is applied in orderto maintain the temperature between 40-50' C. for the entire course of the reduction. Reduction is generally complete at the end of three to four hours of vigorousstirring-atwhichtime the reaction mix- Ina similar manner, with the exception that i for the higher members of this series proportionately larger quantities of water are employed in the reduction, owing to the limited solubilities of the amino ester hydrochlorides in water, the other members of the seriesiwere prepared;

2li'Beta-normal .propyl amino; beta, beta-dimethyl-ethyl para-amino benzoate hydro M. P. =239-240 c; from methano1.-

22. Beia-isopropyl amino beta, beta-dimethyl ethyl para amino benzoate hydrochloride I oooomx J-NHoaHmsofinol CH3 ,INHQ M. P. 234'.5-236.0 c. from H2O. 23., Beta-,N-batyl amino. beta, beta-.dimethyl ethyl pararamino benzoate hydrochloride M. P.=192.0192.5 c. from methanol.

23A; Beta (sec. butyl) amino beta, beta-dimethyl i ethyl para-amino benzoate hydrochloride CH3 CHa O 5H3 C2H5 I NH2 I 24. Beta-isobutyl amino beta, beta-dimethyl ethyl para-amino benzoate hydrochloride (EH3 I COOCHz.(IJ-NH C4Hu(iso) .1101 J M. P.=225.8-228.0 c'. from water.

25. Beta-N-amyl amino beta, beta-dimethyl ethyl para-amino benzoate hydrochloride M. P. =209.o-211.s c. from water? 26. Beta-isoamyl amino beta, beta-dimethyl ethyl para-amino benzoate hydrochloride CH3 l CHs M. P.=202-203 C. froinwatcr.

27. cBeta+N+hearyl=amino beta, beta-dimethyl ethyl I para-aminorbenzoate hydrochloride coooHtc-Nnqln gngiwl 1 M.P.rQ2i2.5 2i3.5C.from water..--.; i

28.: 'Beta- (thyl batyl) amino-beta, beta-dimethyl ethyl para amino benzoate hydrochloride M. P.=19'l.0198.0 C. from water.

30. Beta (alpha-methyl'heptyl) aminobeta, betadimethyl ethyl Para airiino' benzoate hydrochloride COOCH2.C INHCH.CQH1:LHOI

' E- Ha i. .M. -.9. V ,v M. P.=-137 c. from twat er. The forriiate salt; of this compound, white crystals from dioxane, melts at 107-108.5 C.

31. Beta-(beta-ethyl hezcyl) amino-beta, beta dimethyl ethyl para amino benzoate hydrochloride NH: P.=j1 54" 15s'"'c:;" Rec rystafiiza rrom waist. 32. Beta normal decyl amino beta, beta dirnethyl eth l We wh we??? llw h r r t GOOOHz.O.NH,.C1oH2i(n.) H01 Half This is a solid material having an M. P. =141- 142 C.

M. P.=205-209 C. Recrystallized from water.

33. Beta-normal butyl amino beta, beta-dimethyl ethyl ortho amino benzoate 34. Hydrochloride of beta-normal butyl ammo beta, beta-dimethyl ethyl meta amino beneoate M. P.=205-20'l C. Recrystallized from water.

| O CH. NHz

M. P.=186.5187.5 C. Recrystallized from water.

36. Hydrochloride of beta isoamyl amino betamethyl ethyl para amino benzoate Jim M. P.= 195.5196.5 o. Recrystallized from water. 37. Hydroiodz'de of beta-normal butyl amino alpha, beta-dimethyl ethyl para amino benzoate Ha CH3 NH: M. P.=2l4218 C. Recrystallized from water.

The formate salt of this compound, white crystals fromdioxane, melts at 138.2-140.4 C. 38. Hydroiodide of beta-normal amyl amino alpha, beta-dimethyl ethyl para-amino ben-.

M. P.=203-205 C. Recrystallized from water.

39. Hydroiodide of beta-isoamyl amino alpha, beta-dimethyl ethyl para amino benzoate tals from dioxane, melts at 134-136 C. v

has been anesthetized with a single standard dose of the anesthetic and remained anesthetized for a longer period than any other eye anesthetic of which I am aware.

The appended claims are intended to define not only an amino base or bases, but alsoa salt thereof, such as the hydrochloride, sulfate, formate, or the like.

The expression alkyl amino as used in the claims is intended to designate not only the normal amino compounds but also any isomers of the alkyl group. The expressions amyl amino and octyl amino similarly define bot-h normal compounds and isomers. thereof.

While I have described my improvements in great detail and with respect to preferred forms thereof, I do not desire to be limited to such details and forms since many changes and modifications may be made and the invention embodied in widely diiierent forms without departing from the spirit and scope thereof in itsbroader aspects. Hence, I desire to cover all modifications, forms and embodiment coming within the language or scope of any one or more of the appended claims.

What I claim as new and desire tosecure by Letters Patent is: i

1. Beta-alkyl amino. beta, beta-dimethyl ethyl amino benzoate having the formula:

. CH2 NHLCGHLC o o CH2.(|3NH Alkyl I JHz in which the alkyl group contains no more than 10 carbon atoms.

2. Beta-ethyl amino beta, beta-dimethyl ethyl para amino benzoate having the formula:

3.-Beta-amyl amino beta, beta-dimet'hyl ethyl para amino benzoate having the formula:

CHa C O O CH2.(:J.NHCtHu 4. Beta-octyl amino beta, beta-dimethyl ethyl para amino benzoate having the formula:

CH3 C O O CH2.(B.NHC!H17 WILLIAM F. HINGE.

CERTIFICATE OF CORRECTION.

Patent No. 2,565,081. November 21., 19th.

WILLIAM F RINGK.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows: Page 1, first column/line 57, for the word "at" read --as-; page 5, second column, line 57, for "breaker"? read --beaker-; and that the said Letters Patent should be read with this correction therein that the same may conform to the rec- 0rd of file case in the Patent Office.

Signed and sealed this 6th day of February, A. D. 19L

Leslie Frazer (Seal) Acting Commissioner of Patents. 

